JPH09504543A - Cataract prevention methods and preventive measures - Google Patents

Abstract

  (57) [Summary] Described is the use of a thiol-binding prostaglandin or prostaglandin-like compound for the manufacture of a composition for the prevention of cataracts, as well as the use of such compounds for the prevention of cataracts. Preferred compounds include compounds having an α, β-unsaturated ketone in the ring, in particular PGA and PGJ and its derivatives, or one or more α, β-unsaturated ketones in the α and / or ω chains. It is a compound.

Description

Detailed Description of the Invention                        Cataract prevention methods and preventive measures   The present invention provides α, β- for the manufacture of ophthalmically compatible compounds for cataract prevention. Thiol-binding prostag containing unsaturated ketone Landin or prostaglandin-like substance, especially A-type or J-type prostaglandin Relates to the use of gin or an analogue thereof.   Cataract is a common name for opacification of the lens. Cataracts have many causes There are several types. For example, cataract is a metabolic disorder like diabetes mellitus. Manifested by sexually transmitted diseases and various radiations such as X-rays, ultraviolet rays and infrared rays I can do it. However, the most common form of cataract is senile cataract, which It can be considered as normal physiological aging of the lens. Also, local diseases and trauma of the eye are within white. It can lead to the formation of disorders such as chronic iritis and traumatic lesions of the lens. Impermeable Clarification is localized to the entire lens or to specific parts of the lens, such as the nucleus or cortex Alternatively, it may be localized on the surface, eg, the anterior or posterior capsule of the lens. There are also congenital cataracts.   Certain drugs can cause cataracts as a side effect. You. Such agents include, for example, corticosteroids and cholinesterases. Inhibitors are included. At present, the only cure for cataract is surgery. Therefore Remove the opacified lens and implant a synthetic intraocular lens. Usually such The surgery is successful and the patient's vision is restored, but vision-threatening complications can occur. An example For example, about 0.1-0.3% of patients who have undergone surgery suffered from endophthalmitis, which threatens their eyesight. This is equivalent to over 10,000 cases per year worldwide. further , Some risk factors that can adversely affect the outcome of surgery, such as glaucoma, diabetes And there is myopia. Therefore, performing cataract surgery can pose certain risks and delay surgery. There are patients that are desirable to treat.   Much research has been done on the treatment or prevention of cataracts to reverse the formation of cataracts. Several drugs have been suggested to start or stop, but such drugs are effective Whether or not there is still debate. That the drug has a real therapeutic effect No scientific evidence exists so far. Formation of large aggregates of proteins, phase separation Maximum critical temperature for separation, implications for increasing Tc, and action of certain reagents , For example, Pande et al., Exp Eye Res 57 (19). 93) 257-264, Pande's Exp Eye Res 681 (Supplementary Note) 1) 197 and Truscott et al. Exp Eye Res 49 (1989). ) 927-940.   Applicants have found that certain prostaglandins and prostaglandin-like substances (such as In the specification, included in the term "prostaglandin") We unexpectedly found that it effectively prevents or delays the formation of disorders. More specific Specifically speaking, such compounds containing α, β-unsaturated ketones (enones), in particular Compounds containing α, β-unsaturated ketone (enone) in the clopentane ring are effective It was discovered. The prostaglandin group especially includes A-type and J-type prostaglandins. (See definition below) and various derivatives and analogs thereof. I However, all prostaglandins have lower side chains (ω chains) after the initial metabolic degradation. With α, β-unsaturated ketones and therefore can have a similar effect, and It may be of significant importance, but for use in the present invention, the cyclopentane ring contains α And prostaglandin analogs containing β-unsaturated ketones Is preferred.   The general structure of prostaglandins is shown below:   Prostaglandins A, B, C, D, E, F and J are cyclopentane ring and It contains two side chains, the upper side chain is the α chain and the lower side chain is the ω chain. carbon The total number of atoms is 20, and the number starts with the carboxyl group of the α chain. α chain is charcoal While there is a cis double bond between elementary atoms 5 and 6, the ω chain has carbon atom 13 It has a double bond between 14 in a trans form. Therefore, the above two double bonds The number 2 is added to the end of the prostaglandins that it has, and there are 5,6 double bonds in the α chain. If there is no, the number 1 is added to the end. Therefore, a probe containing two double bonds Rostaglandin is PGA₂, PGB₂, PGC₂, PGD₂, PGE₂, PGF_{2 a} , PGJ₂And a prostaglandin containing one double bond is called PGA.₁, P GB₁, PGC₁And so on. In addition, some prostaglandins contain carbon It may contain a third double bond between atoms 17 and 18, which double bond Indicates a cis configuration. These are PGA_Three, PGB3, PGC_Three, PGD_ThreeWhat Is called.   Depending on the configuration of the cyclopentane ring (X) and the substituent, the prostaglandin can be It is determined whether it is of type A, B, C, D, E, F or J. Cyclope The various configurations of the tan ring are shown below:   Among these, A-type and J-type prostaglandins and their derivatives are It is particularly important because it contains an α, β-unsaturated ketone in the clopentane ring. α, β-unsaturated ketones are very reactive and can react with thiol groups such as proteins Form an adduct with the above sulfhydryl group. Therefore, such thiol bond Prostaglandin having a thiol-binding group Reacts with the crystalline of the lens to form a thiol adduct, As a result, disulfide bridges between sulfhydryl group lens proteins can be formed. To prevent formation and thus to oxidative stress To prevent protein aggregation.   In one embodiment of the invention, the cyclopentane ring is an α, β-unsaturated keto A prostaglandin-type compound containing benzene is used. Of these types of substances Examples include PGA in which the sulfhydryl group is attached to carbons 11 and 9 respectively and PGJ is included.   PGA having specific cyclopentane ring configuration_1-3Or PGJ_1-3Any invitation of Conductors as well as similar molecules designed to exhibit such functional properties are useful in the present invention Can be predicted. In this regard, type A or type J stabilized prostaglandins, eg For example, △⁷-PGA₂And △¹²-PGJ₂Seems to be important.   Certain prostaglandins have significant biological effects, for example in the eye It is known to use various derivatives for the treatment of glaucoma and hypertension Several patent applications have been filed (eg EP 093380, WO 90/02553 and EP 0344235 See). Among these, prostaglandins containing ring-substituted ω chains, Especially, those having a phenyl substituent on carbon 17 are extremely effective and have no side effects. It was found to be either poor or almost absent.   This is the most important thing. This is because the prosta to be used according to the invention Glandin has no biological activity except for the sulfhydryl group-binding ability of proteins. This is because it is characterized by having no or only weak activity. Prostag An adduct or complex formed between a lundine compound and a lens protein (com Plex) is used to reduce the required dose of active compound and the frequency of application. It must have a high production constant.   Therefore, from such prostaglandins, eg, A-type and J-type derivatives, All typical side effects of prostaglandins that can be detrimental to the eye, eg irritation And conjunctival hyperemia (reddening of the eye) and pigmentation of the iris of the eye, and in other applications It is necessary to eliminate the desired biological activity, for example the effect of reducing intraocular pressure .   Therefore, by producing novel prostaglandin type A and J type molecules, It can be used to prevent the formation of disorders.   An important feature of the A-type and J-type prostaglandins is that, as mentioned above, cyclopenes It is an α, β-unsaturated ketone having a tan ring (X). Ω for additional α, β-unsaturated ketone Introduced into the chain and the α-chain, the bifunctional or multifunctional molecule with respect to thiol binding activity Of course,   Therefore, the prostaglandin derivative or analog to be used in the present invention has the structure [Wherein the ring is a 5- to 7-membered ring containing an α, β-unsaturated ketone, for example, And the ring is, for example, one or more having 1 to 6, especially 1 to 4 carbon atoms. Optionally substituted with a lower alkyl group] Can be generalized to   R₁Is H or lower alkyl as defined above.   The α and ω chains may have the above structure associated with natural prostaglandins. However, in general, a carbon chain Z-R (where Z is 4-10 carbon atoms and optionally Containing one or more α, β-unsaturated ketones). Same or different α chain The ω chain is optionally substituted with one or more alkyl groups, especially lower alkyl groups as defined above. Will be replaced.   R is hydrogen or an alkyl group, preferably 1-10, especially 1-6, for example A group having 1 to 4 carbon atoms, or a group C (O) -OR₂(Where R₂Is Hydrogen, or an alkyl group having 1 to 10, especially 1 to 6 carbon atoms, for example , Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl Or benzyl) or an aromatic ring such as phenyl or 5 Aromatic heterocyclic groups having 6 to 6 ring atoms, for example thiazole, imidazole, pyridine Rolidine, thiophene and oxazole, or a system having 3 to 7 atoms in the ring. Selected from the group consisting of chloroalkanes or cycloalkenes, optionally defined above. It is a ring structure substituted with a meaningful alkyl group.   The ω-chain as well as the α-chain are optionally, preferably at most one It may be blocked at the heteroatoms O, S or N.   The α and ω chains have the structure shown in the general description of prostaglandins above. Can have. In a preferred embodiment of the invention one or both of the chains is Construction: (Where R is as defined above) And an α, β-unsaturated ketone exemplified by   To administer prostaglandins or their derivatives locally to the eye, various Lipophilic prodrugs of Such prodrugs include those indicated above. Represented by the general formula, for example, an ester having 1 to 10 carbon atoms (for example, Alkyl esters) and especially esters having 1 to 6 carbon atoms. Such esters include, for example, methyl, ethyl, propyl, isopropyl, Includes butyl, isobutyl, neopentyl and benzyl. Hydroxy on the side chain For example, a silyl group can be formed with pivalolic acid or butyric acid. Even if esterified Good. Alternative lipophilic prodrugs include amides. Prostaglandin Sodium, chloride or tromethamine depending on the chemical properties of Amine) salts such as salts may be used.   The compounds are physiologically aqueous or oily solutions in the ophthalmically acceptable pH range. It can be prepared as an acceptable solution. To enhance the penetration of the compound into the eye, Thickeners such as hydroxypropylmethyl cellulose, polyvinyl alcohol , Polyvinylpyrrolidone, hyaluronic acid and other polymers known for the eye It may be used in the preparation of the invention, which further comprises a prostaglandin solubilizer and And stabilizers, such as systems with cyclodextrin or analogs thereof. Enhanced drug penetration into the eye using sustained release matrices, gels or solid inserts However, the required number of applications can be reduced. Such formulations containing the active compound are , Benzalkonium chloride or other preservatives such as chlorhexidine, chlorobutane Tanols, para-hydroxybenzoic acid and phenylmercuric acid salts, eg nitrates, salts Compounds, acetates, borates and the like may be added for storage. The preparation further comprises additives, For example, EDTA, EGTA, sorbitol, ho It may include uric acid and the like and may be enclosed in a multi-dose dispenser. Alternatively, The preparation may be enclosed in a single dose dispenser, in which case a preservative will be added to the preparation. It may or may not be added.   Typically, new agents to prevent cataracts are taken 1 to 4 times daily, It is necessary to administer to the eye locally at regular intervals, usually over a long period of time or intermittently. You. Intermittent means that there is a period of no treatment after the period of treatment with the active ingredient, and This means that the treatment with the active ingredient is repeated again. Depending on the sustained-release preparation, soft Quality or hard eye drop inserts, eg once a week, or once a month, or longer The drug may be administered continuously by exchanging at intervals.   The dose to be used for local treatment depends on the specific prostaglandin compound and its substance. It may change depending on physicochemical properties. The ophthalmic composition is typically 0.001-10. Must contain mg / ml, especially 0.1-10 mg / ml of active ingredient Yes.   Related in vitro model and presently preferred as new active ingredient for cataract prevention Active compounds PGA₂-Tromethami The present invention is illustrated by the following non-limiting examples using salt salts.   PGA in methanol (3.0 ml)₂(Cayman Chemicals 30 mg, 0.0897 mmol) solution, tris (hydroxymethyl) -a Minoethane (10.8 mg; 0.0897 mmol) was added. Mix at room temperature Stir vigorously for 3 hours. The solvent was removed under vacuum and PGA as a pale yellow oil₂ -41 mg of tromethamine salt was obtained.B. Prevention of cataract formation in vitro   The experiment was performed using a bovine lens. The lens is placed within 5-6 hours after death after the eye. I took it out from the department. Take out the lens together with the capsule so as not to damage it 1 It was placed in 5 ml of phosphate buffer solution (pH 7.5). Divide the lens into two groups And one group 10 in phosphate buffer^-3Prostaglandin at final concentration of M A₂Incubate with tromethamine salt and the other group in phosphate buffer Incubated with chisels. After incubating for 24 hours at room temperature, the lens To a final concentration of 0.2% hydrogen peroxide (H₂O₂), 39-40 Oxidation storage at Was added, but half of the sample was prostaglandin A₂With tromethamine salt, after Half of these did not contain the salt. Furthermore, PGA₂-Prepare with tromethamine salt Incubated one lens and PGA₂− Pre-incubate with tromethamine salt The same lens that was not used₂O₂Incubate without Incubation medium and used as negative control.   At regular intervals within 24 hours after starting the incubation with hydrogen peroxide I took a color photo at. A vial containing the lens in the incubation medium, Place on a grid pattern drawn on paper, put the crystalline lens through and see how the grid pattern looks The degree of disability was evaluated. We used grades from 0 to 3, where 0 is a completely transparent lens, 1 is a slightly opacified lens, 2 is a medium opacified lens, 3 is through the lens And shows a complete cataract with virtually no visible grid pattern.   PGA₂-Lens pre-incubated with tromethamine salt, PGA₂− Lenses that were not preincubated with lomethamine salt (positive control) as well as negative The results of the experiments with sex controls are shown in Table I.   As you can see from Table I, PGA₂-Preincubation with tromethamine salt The crystalline lens is PGA₂-No preincubation with tromethamine salt It was less opaque and much slower to opaque than the positive control lens. Excessive Lenses (C-1 and C) without any hydrogen oxide attack (challenge) -2) showed no opacity or only a very slight opacity. This is because of the transparency of the lens even after incubation at 39-40 ° C for 24 hours. Showing that it had no or only a negligible effect on I have.   These experiments show that at 39-40 ° C., it is significantly more like a 0.2% hydrogen peroxide solution. PGA even when using oxidation₂Confirmed that protects the lens from oxidative damage Is done. Under clinical conditions, the degree of oxidative stress applied to the lens is Much less than that used in the Ming experiment, cataracts usually last for years or It progresses in several decades. Therefore, even with much smaller amounts of active ingredient, lens oxidation And can be expected to have a protective effect against other injuries, It may be administered topically to the eye at regular intervals.

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Claims (1)

[Claims] 1. Use of an eye-compatible thiol-binding prostaglandin or prostaglandin-like compound for the manufacture of an eye drop for the prevention of cataracts. 2. Use according to claim 1, wherein the prostaglandins are of type A or type J, especially type A ₂ or type J ₂ . 3. Prostaglandin or prostaglandin-like compounds, esters, preferably, use according to claim 1 or 2 is a C ₁ -C ₁₀ esters, amides or salts. 4. A composition for topical administration to the eye, comprising an effective amount of at least one thiol-binding prostaglandin or prostaglandin-like compound and an eye-compatible carrier. 5. A method for preventing cataract by administering to the eye a formulation compatible with the eye, which comprises a thiol-binding prostaglandin or a prostaglandin-like compound capable of forming an adduct with a lens protein. 6. The method according to claim 5, wherein the prostaglandin is of type A or type J, especially type A ₂ or type J ₂ . 7. Prostaglandin or prostaglandin-like compounds, esters, preferably, C ₁ -C ₁₀ esters, method according to claim 5 or 6 is an amide or salt. 8. 8. The method according to any one of claims 5 to 7, which comprises topical administration to the eye.